The delivery of therapeutics to the lung for the local treatment of pulmonary disorders (asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis) has long been utilized, and inhalation therapy for the treatment of systemic diseases (e.g. diabetes) has been the focus of increasing academic and industry research within the past decade. Given its extremely large surface area, mild environment, and ease of administration, in contrast to oral and intravenous routes of drug delivery, the lung presents an especially attractive avenue of therapeutic delivery.
However, pulmonary drug delivery is not without its obstacles. For drug particles to deposit in the deep lung, where they exert their therapeutic action, they must possess certain physical properties. Specifically, the drug particles must have an average aerodynamic diameter below 5 microns, where the average aerodynamic diameter encompasses both the density and geometric diameter of the drug particle. Accordingly, aerosolized drug particles must be less than 5 microns in average aerodynamic diameter when they exit an inhaler to deposit in the deep lung. While both liquid (metered dose inhalers, nebulizers) and solid (dry powder inhalers) dosage forms are used for inhalation therapy, dry powder drug formulations are garnering an increasing share of the market due to their dose flexibility and excellent drug stability.
Dry powder formulations are generally binary mixtures comprised of fine drug particles (<5 microns) and coarse carrier particles (generally between 30 and 90 microns) blended together at a ratio of approximately 2% drug and 98% carrier (w/w). Due to the micron dimensions of the drug particles, the cohesive forces that exist between them, due primarily to Van der Waals and electrostatic forces, are quite strong and prevent drug particles from being readily deaggregated as they exit the inhaler. Even while the primary particle size (i.e., the size of a single particle of the drug powder) may be below 5 microns in diameter, a large fraction of the dose is agglomerated drug particles many times the size of the primary particles, leading to drug deposition in the mouth, throat, or upper airways, and possibly producing toxic side effects. The use of coarse carrier particles aids in the entrainment and dispersion of the formulation in the flow stream produced when a patient inhales through a dry powder inhaler.
Mixing the two component powders together is typically performed through a mechanical process, where the drug and carrier particles are placed in a metal or glass container, which is then spun and rotated in an orbital mixer for a period generally exceeding 30 minutes. The continuous contact between the drug and carrier particles serves to break apart drug aggregates and replace cohesive (drug-drug) interactions with adhesive (drug-carrier) interactions.
While dry powder formulations offer many advantages over liquid formulations, their performance is plagued by low drug delivery (generally below 30% of the total dose is delivered to the deep lung) and high throat and upper airway deposition. This is evidence that the majority of the drug particles exiting the inhaler are not in the primary particle size (<5 microns), but rather in agglomerates or still attached to carrier particles, which due to their large average aerodynamic diameter deposit in the throat and upper airways. Thus, the problems with blending drug and carrier particles through a mechanical process is that drug-drug cohesive interactions are not effectively eliminated, and press-on forces between drug and carrier particles can be large enough to prevent the detachment of the drug from the carrier particle during inhalation. Additionally, the use of mechanical processes to blend drug and carrier particles can also lead to milling of the drug particles, where the primary drug particles are fragmented during mixing, exposing high energy sites that bind tightly with either drug particles or carrier particles, preventing their dispersion.
A further problem arises when the size of the carrier particles is increased. For 2% drug/carrier particle blends (w/w) with carrier particles between 30 and 90 microns in diameter, the total surface area of the carrier particles is large enough to theoretically allow the fine drug particles to form a monolayer coating on the coarse carriers (although in practice many drug particles remain aggregated following blending). For powder of the same mass, as the size of the carrier is increased, the total surface area is reduced, and the drug can no longer form a monolayer of primary particles, and multiple layers of drug now coat the surface of the carriers. This is undesirable, as the strong cohesive interactions between the drug particles will preclude their dispersion into particles sized for deep lung delivery.
It may be desirable to provide a system and method for dosing and coating inhalation powders onto carrier particles that deaggregates drug powder into particles of primary size and reduces the presence and subsequent dispersion of drug agglomerates that could undesirably deposit in the mouth and upper airways. It may also be desirable to provide a system and method for coating carrier materials with drug particles sized to be deposited in the deep lung, improving the efficacy of current dry powder inhalers. It may also be desirable to provide a system and method that reduces the instances of tightly bound drug-carrier interactions.